Abstract: During the first phase of the AMDCC our group at TJU studied the decorin KO diabetic mouse. Our hypothesis was that decorin acts as an endogenous protective factor by inhibiting active TGF-b. We found that decorin is indeed protective, as decorin KO mice had accelerated kidney disease and surprisingly increased mortality. Based on our results, the AMDCC investigators as a group chose the decorin KO diabetic mouse as a leading success during the 1st funding period. Of major mechanistic interest, we found that decorin KO diabetic mice that died exhibited evidence of renal insufficiency and low plasma adiponectin levels, months prior to mortality. This is similar to the human clinical condition. Low adiponectin levels are a powerful biomarker of increased cardiovascular morbidity and mortality in patients with kidney disease. Additionally, the decorin KO mice had increased NADPH oxidase (Nox4) expression in the kidney which may contribute to more severe nephropathy. In the next phase of the AMDCC, we propose test the following hypotheses. 1. Deficiency of adiponectin in combination with lack of decorin leads to enhanced lethality and diabetic nephropathy and 2. Increased Nox4 in vascular smooth muscle cells enhances diabetic nephropathy and the vascular complications of diabetic kidney disease. We propose to generate new diabetic mouse models by crossing adiponectin KO mice with decorin KO mice and by generating mice transgenic for smooth muscle Nox4 using the SM22 promoter. Diabetes will be induced by crossing with Akita mice. These mice will be characterized for diabetic nephropathy and cardiovascular disease. Both new models will be fully characterized for diabetic nephropathy. More importantly, we propose a series of interventional studies to test the causal role of TGF-b, adiponectin, and Nox4 in the pathogenesis of accelerated diabetic nephropathy. Key features we will focus on include matrix accumulation, renal function, autoregulation, and mortality. The proposed studies are directly related to the human condition, in which TGF-(, adiponectin, and Nox4 are key biomarkers for worse disease, but their pathogenetic role is unproven. Our findings will advance our mechanistic understanding of diabetic nephropathy and vascular disease and may lead to better biomarkers and novel treatments.

Diabetic kidney and nerve disease in patients is associated with glycemia control. Initial studies revealed that mice with diabetes have a correlation with hyperglycemia and kidney disease. Int he present proposal we will determine if different mouse strains have different relationships between hyperglycemia and kidney and nerve disease and if gender is also an important variable.

Hyperglycemia and diabetic kidney and nerve disease

The proposed summer student application will seek to mine the AMDCC database to evaluate two key questions, 1. Does the degree of hyperglycemia correlate with the diabetic kidney and nerve complications, and 2. Are features of diabetic kidney and nerve disease track with each other? To answer these questions there will be a joint mentorship to guide several talented students for the summer period. Several new mouse models with diabetes have been developed by the AMDCC and their data has been deposited in the AMDCC website. With the information already available, the question of whether the plasma glucose levels across the duration of diabetes will be correlated with albuminuria and plasma creatinine levels (as markers of kidney function) as well as nerve conduction velocity and sensory loss (as markers of neuropathy) in aim 1. In aim 2, the data describing the quantitation of albuminuria and mesangial matrix will be correlated with nerve dysfunction. Data will be analyzed with the assistance of a tema of mentors that will include Dr. Sharma (for nephropathy), Dr. Nigel Calcutt for neuropathy, Dr. Tim Ravasi (for bioinformatic support) and Dr. Ronghui (Lily) Xu (for biostatistical support). Students will include one college student and two high school students who have some expertise basic biology research, bioinformatic analysis, and mouse models.